Involvement of the opioid system in the anxiolytic effect of diazepam in mice

In the present study, the anticonflict effect of diazepam was significantly abolished by pretreatment with naloxone, beta-funaltrexamine or nor-binaltorphimine but not naltrindole, using a Vogel-type conflict paradigm in mice. However, naloxone alone had a significant proconflict effect, and beta-funaltrexamine alone tended to produce a proconflict effect. Spontaneous drinking behavior was not affected by treatment with diazepam and nor-binaltorphimine. In addition, nor-binaltorphimine had no effect on diazepam-induced motor incoordination, hypothermia or anticonvulsant action, respectively. Moreover, the stable dynorphin analog E2078 ([N-methyl-Tyr(1),N-alpha-methyl-Arg(7),D-Leu(8)]dynorphin A-(1-8) ethylamide) and the highly selective kappa-opioid receptor agonist U50,488H (trans-3,4-dicloro-N-(2-(1-pyrrolidinyl)cyclohexyl)benzenacetamide methanesulfonate hydrochloride) produced a significant anticonflict effect, which was completely antagonized by pretreatment with nor-binaltorphimine. These findings suggested that the kappa-opioid system may play an important role in the anxiolytic effect of benzodiazepines and the regulation of anxiety.